Showing papers by "University of Zurich published in 2005"

Effects of biodiversity on ecosystem functioning: a consensus of current knowledge

Abstract: Humans are altering the composition of biological communities through a variety of activities that increase rates of species invasions and species extinctions, at all scales, from local to global. These changes in components of the Earth's biodiversity cause concern for ethical and aesthetic reasons, but they also have a strong potential to alter ecosystem properties and the goods and services they provide to humanity. Ecological experiments, observations, and theoretical developments show that ecosystem properties depend greatly on biodiversity in terms of the functional characteristics of organisms present in the ecosystem and the distribution and abundance of those organisms over space and time. Species effects act in concert with the effects of climate, resource availability, and disturbance regimes in influencing ecosystem properties. Human activities can modify all of the above factors; here we focus on modification of these biotic controls. The scientific community has come to a broad consensus on many aspects of the re- lationship between biodiversity and ecosystem functioning, including many points relevant to management of ecosystems. Further progress will require integration of knowledge about biotic and abiotic controls on ecosystem properties, how ecological communities are struc- tured, and the forces driving species extinctions and invasions. To strengthen links to policy and management, we also need to integrate our ecological knowledge with understanding of the social and economic constraints of potential management practices. Understanding this complexity, while taking strong steps to minimize current losses of species, is necessary for responsible management of Earth's ecosystems and the diverse biota they contain.

Oxytocin increases trust in humans

Abstract: Trust pervades human societies. Trust is indispensable in friendship, love, families and organizations, and plays a key role in economic exchange and politics. In the absence of trust among trading partners, market transactions break down. In the absence of trust in a country's institutions and leaders, political legitimacy breaks down. Much recent evidence indicates that trust contributes to economic, political and social success. Little is known, however, about the biological basis of trust among humans. Here we show that intranasal administration of oxytocin, a neuropeptide that plays a key role in social attachment and affiliation in non-human mammals, causes a substantial increase in trust among humans, thereby greatly increasing the benefits from social interactions. We also show that the effect of oxytocin on trust is not due to a general increase in the readiness to bear risks. On the contrary, oxytocin specifically affects an individual's willingness to accept social risks arising through interpersonal interactions. These results concur with animal research suggesting an essential role for oxytocin as a biological basis of prosocial approach behaviour.

Classification of cell death: recommendations of the Nomenclature Committee on Cell Death

Abstract: Different types of cell death are often defined by morphological criteria, without a clear reference to precise biochemical mechanisms. The Nomenclature Committee on Cell Death (NCCD) proposes unified criteria for the definition of cell death and of its different morphologies, while formulating several caveats against the misuse of words and concepts that slow down progress in the area of cell death research. Authors, reviewers and editors of scientific periodicals are invited to abandon expressions like 'percentage apoptosis' and to replace them with more accurate descriptions of the biochemical and cellular parameters that are actually measured. Moreover, at the present stage, it should be accepted that caspase-independent mechanisms can cooperate with (or substitute for) caspases in the execution of lethal signaling pathways and that 'autophagic cell death' is a type of cell death occurring together with (but not necessarily by) autophagic vacuolization. This study details the 2009 recommendations of the NCCD on the use of cell death-related terminology including 'entosis', 'mitotic catastrophe', 'necrosis', 'necroptosis' and 'pyroptosis'.

The Social Influence of Brand Community: Evidence from European Car Clubs

Abstract: The authors develop and estimate a conceptual model of how different aspects of customers' relationships with the brand community influence their intentions and behaviors. The authors describe how identification with the brand community leads to positive consequences, such as greater community engagement, and negative consequences, such as normative community pressure and (ultimately) reactance. They examine the moderating effects of customers' brand knowledge and the brand community's size and test their hypotheses by estimating a structural equation model with survey data from a sample of European car club members.

Immunology of multiple sclerosis

Abstract: Multiple sclerosis (MS) develops in young adults with a complex predisposing genetic trait and probably requires an inciting environmental insult such as a viral infection to trigger the disease. The activation of CD4+ autoreactive T cells and their differentiation into a Th1 phenotype are a crucial events in the initial steps, and these cells are probably also important players in the long-term evolution of the disease. Damage of the target tissue, the central nervous system, is, however, most likely mediated by other components of the immune system, such as antibodies, complement, CD8+ T cells, and factors produced by innate immune cells. Perturbations in immunomodulatory networks that include Th2 cells, regulatory CD4+ T cells, NK cells, and others may in part be responsible for the relapsing-remitting or chronic progressive nature of the disease. However, an important paradigmatic shift in the study of MS has occurred in the past decade. It is now clear that MS is not just a disease of the immune system, but that factors contributed by the central nervous system are equally important and must be considered in the future.

“Economic man” in cross-cultural perspective: Behavioral experiments in 15 small-scale societies

Abstract: Researchers from across the social sciences have found consistent deviations from the predictions of the canonical model of self-interest in hundreds of experiments from around the world. This research, however, cannot determine whether the uniformity re- sults from universal patterns of human behavior or from the limited cultural variation available among the university students used in virtually all prior experimental work. To address this, we undertook a cross-cultural study of behavior in ultimatum, public goods, and dictator games in a range of small-scale societies exhibiting a wide variety of economic and cultural conditions. We found, first, that the canonical model - based on self-interest - fails in all of the societies studied. Second, our data reveal substantially more behavioral vari- ability across social groups than has been found in previous research. Third, group-level differences in economic organization and the structure of social interactions explain a substantial portion of the behavioral variation across societies: the higher the degree of market integration and the higher the payoffs to cooperation in everyday life, the greater the level of prosociality expressed in experimental games. Fourth, the available individual-level economic and demographic variables do not consistently explain game behavior, either within or across groups. Fifth, in many cases experimental play appears to reflect the common interactional patterns of everyday life.

Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas.

Abstract: Published data on prognostic and predictive factors in patients with gliomas are largely based on clinical trials and hospital-based studies. This review summarizes data on incidence rates, survival, and genetic alterations from population-based studies of astrocytic and oligodendrogliomas that were carried out in the Canton of Zurich, Switzerland (approximately 1.16 million inhabitants). A total of 987 cases were diagnosed between 1980 and 1994 and patients were followed up at least until 1999. While survival rates for pilocytic astrocytomas were excellent (96% at 10 years), the prognosis of diffusely infiltrating gliomas was poorer, with median survival times (MST) of 5.6 years for low-grade astrocytoma WHO grade II, 1.6 years for anaplastic astrocytoma grade III, and 0.4 years for glioblastoma. For oligodendrogliomas the MSTwas 11.6 years for grade II and 3.5 years for grade III. TP53 mutations were most frequent in gemistocytic astrocytomas (88%), followed by fibrillary astrocytomas (53%) and oligoastrocytomas (44%), but infrequent (13%) in oligodendrogliomas. LOH 1p/19q typically occurred in tumors without TP53 mutations and were most frequent in oligodendrogliomas (69%), followed by oligoastrocytomas (45%), but were rare in fibrillary astrocytomas (7%) and absent in gemistocytic astrocytomas. Glioblastomas were most frequent (3.55 cases per 100,000 persons per year) adjusted to the European Standard Population, amounting to 69% of total incident cases. Observed survival rates were 42.4% at 6 months, 17.7% at one year, and 3.3% at 2 years. For all age groups, survival was inversely correlated with age, ranging from an MST of 8.8 months ( 80 years). In glioblastomas, LOH 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16INK4a deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations, and was the only alteration associated with shorter survival of glioblastoma patients. Primary (de novo) glioblastomas prevailed (95%), while secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hot-spot codons 248 and 273, while in primary glioblastomas, mutations were more evenly distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas, suggesting that the acquisition of TP53 mutations in these glioblastoma subtypes may occur through different mechanisms.

Epidemiology and etiology of gliomas

Abstract: Gliomas of astrocytic, oligodendroglial and ependymal origin account for more than 70% of all brain tumors. The most frequent (65%) and most malignant histological type is the glioblastoma. Since the introduction of computerized tomography and magnetic resonance imaging, the incidence rates of brain tumors have been rather stable, with a tendency of higher rates in highly developed, industrialized countries. Some reports indicate that Caucasians have higher incidence than black or Asian populations, but to some extent, this may reflect socio-economic differences and under-ascertainment in some regions, rather than a significant difference in genetic susceptibility. With the exception of pilocytic astrocytomas, the prognosis of glioma patients is still poor. Less than 3% of glioblastoma patients are still alive at 5 years after diagnosis, higher age being the most significant predictor of poor outcome. Brain tumors are a component of several inherited tumor syndromes, but the prevalence of these syndromes is very low. Several occupations, environmental carcinogens, and diet (N-nitroso compounds) have been reported to be associated with an elevated glioma risk, but the only environmental factor unequivocally associated with an increased risk of brain tumors, including gliomas, is therapeutic X-irradiation. In particular, children treated with X-irradiation for acute lymphoblastic leukemia show a significantly elevated risk of developing gliomas and primitive neuroectodermal tumor (PNET), often within 10 years after therapy. TP53 mutations are frequent in low-grade gliomas and secondary glioblastomas derived therefrom. Approximately 60% of mutations are located in the hot spot codons 248 and 273, and the majority of these are G:C→A:T transitions at CpG sites. TP53 mutations are significantly more frequent in low-grade astrocytomas with promoter methylation of the O 6 -methylguanine-DNA methyltransferase repair gene, suggesting that, in addition to deamination of 5-methylcytosine, exogenous or endogenous alkylation in the O 6 position of guanine may contribute to the formation of these mutations.

Accuracy of MSCT coronary angiography with 64-slice technology: first experience.

Abstract: Aims The aim of our study was to investigate the accuracy of 64-slice computed tomography (CT) for assessing haemodynamically significant stenoses of coronary arteries. Methods and results CT angiography was performed in 67 patients (50 male, 17 female; mean age 60.1±10.5 years) with suspected coronary artery disease and compared with invasive coronary angiography. All vessels ≥1.5 mm were considered for the assessment of significant coronary artery stenosis (diameter reduction >50%). Forty-seven patients were identified as having significant coronary stenoses on invasive angiography with 18% (176/1005) affected segments. None of the coronary segments needed to be excluded from analysis. CT correctly identified all 20 patients having no significant stenosis on invasive angiography. Overall sensitivity for classifying stenoses was 94%, specificity was 97%, positive predictive value was 87%, and negative predictive value was 99%. Conclusion Sixty-four-slice CT provides a high diagnostic accuracy in assessing coronary artery stenoses.

Treatment of painful pseudoparesis due to irreparable rotator cuff dysfunction with the Delta III reverse-ball-and-socket total shoulder prosthesis.

Abstract: Background: The Delta III reverse-ball-and-socket total shoulder implant is designed to restore overhead shoulder function in the presence of irreparable rotator cuff deficiency by using the intact deltoid muscle and the stability provided by the prosthetic design. Our purpose was to evaluate the clinical and radiographic results of this arthroplasty in a consecutive series of shoulders with painful pseudoparesis due to irreversible loss of rotator cuff function. Methods: Fifty-eight consecutive patients with moderate-to-severe shoulder pain and active anterior elevation of <90° due to an irreparable rotator cuff tear were treated with a Delta III total shoulder replacement at an average age of sixty-eight years. Seventeen of the procedures were the primary treatment for the shoulder, and forty-one were revisions. The patients were examined clinically and radiographically after an average duration of follow-up of thirty-eight months. Results: On the average, the subjective shoulder value increased from 18% preoperatively to 56% postoperatively (p < 0.0001); the relative Constant score, from 29% to 64% (p < 0.0001); the Constant score for pain, from 5.2 to 10.5 points (p < 0.0001); active anterior elevation, from 42° to 100° (p < 0.0001); and active abduction, from 43° to 90° (p < 0.0001). The patients for whom the implantation of the Delta III prosthesis was the primary procedure and those who had had previous surgery showed similar amounts of improvement. The total complication rate, including all minor complications, was 50%, and the reoperation rate was 33%. Of the seventeen primary operations, 47% (eight) were associated with a complication and 18% (three) were followed by a reoperation. Of the forty-one revisions, 51% (twenty-one) were associated with a complication and 39% (sixteen) were followed by a reoperation. Subjective results and satisfaction rates were not influenced by complications or reoperations when the prosthesis had been retained. Conclusions: Total shoulder arthroplasty with the Delta III prosthesis is a salvage procedure for severe shoulder dysfunction caused by an irreparable rotator cuff tear associated with other glenohumeral lesions. Complications were frequent following both primary and revision procedures, but they rarely affected the final outcome. The procedure has a substantial potential to improve the condition of patients with severe shoulder dysfunction, at least in the short term. Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Integration of Oxygen Signaling at the Consensus HRE

Abstract: The hypoxia-inducible factor 1 (HIF-1) was initially identified as a transcription factor that regulated erythropoietin gene expression in response to a decrease in oxygen availability in kidney tissue. Subsequently, a family of oxygen-dependent protein hydroxylases was found to regulate the abundance and activity of three oxygen-sensitive HIFalpha subunits, which, as part of the HIF heterodimer, regulated the transcription of at least 70 different effector genes. In addition to responding to a decrease in tissue oxygenation, HIF is proactively induced, even under normoxic conditions, in response to stimuli that lead to cell growth, ultimately leading to higher oxygen consumption. The growing cell thus profits from an anticipatory increase in HIF-dependent target gene expression. Growth stimuli-activated signaling pathways that influence the abundance and activity of HIFs include pathways in which kinases are activated and pathways in which reactive oxygen species are liberated. These pathways signal to the HIF protein hydroxylases, as well as to HIF itself, by means of covalent or redox modifications and protein-protein interactions. The final point of integration of all of these pathways is the hypoxia-response element (HRE) of effector genes. Here, we provide comprehensive compilations of the known growth stimuli that promote increases in HIF abundance, of protein-protein interactions involving HIF, and of the known HIF effector genes. The consensus HRE derived from a comparison of the HREs of these HIF effectors will be useful for identification of novel HIF target genes, design of oxygen-regulated gene therapy, and prediction of effects of future drugs targeting the HIF system.

Phenotypic and genetic differentiation between native and introduced plant populations

Abstract: Plant invasions often involve rapid evolutionary change. Founder effects, hybridization, and adaptation to novel environments cause genetic differentiation between native and introduced populations and may contribute to the success of invaders. An influential idea in this context has been the Evolution of Increased Competitive Ability (EICA) hypothesis. It proposes that after enemy release plants rapidly evolve to be less defended but more competitive, thereby increasing plant vigour in introduced populations. To detect evolutionary change in invaders, comparative studies of native versus introduced populations are needed. Here, we review the current empirical evidence from: (1) comparisons of phenotypic variation in natural populations; (2) comparisons of molecular variation with neutral genetic markers; (3) comparisons of quantitative genetic variation in a common environment; and (4) comparisons of phenotypic plasticity across different environments. Field data suggest that increased vigour and reduced herbivory are common in introduced plant populations. In molecular studies, the genetic diversity of introduced populations was not consistently different from that of native populations. Multiple introductions of invasive plants appear to be the rule rather than the exception. In tests of the EICA hypothesis in a common environment, several found increased growth or decreased resistance in introduced populations. However, few provided a full test of the EICA hypothesis by addressing growth and defence in the same species. Overall, there is reasonable empirical evidence to suggest that genetic differentiation through rapid evolutionary change is important in plant invasions. We discuss conceptual and methodological issues associated with cross-continental comparisons and make recommendations for future research. When testing for EICA, greater emphasis should be put on competitive ability and plant tolerance. Moreover, it is important to address evolutionary change in characteristics other than defence and growth that could play a role in plant invasions.

Spektroskopische Methoden in der organischen Chemie

Abstract: Spektroskopische Methoden im Uberblick 3-9 Einfuhrung in die Schwingungsspektroskopie (IR) 10-19 Mechanismen der Schwingungsanregung 20-23 Prinzip der Raman-Spektroskopie 24-30 Schwingungsfrequenz 31-39 Grundschwingungen und Schwingungen hoherer Ordnung 40-44 Spektreninterpretation 45-62 Molekulsymmetrie und Schwingungsaktivitat 63-81

The Economics of Fairness, Reciprocity and Altruism--Experimental Evidence and New Theories.

Abstract: Most economic models are based on the self-interest hypothesis that assumes that material self-interest exclusively motivates all people. Experimental economists have gathered overwhelming evidence in recent years, however, that systematically refutes the self-interest hypothesis, suggesting that concerns for altruism, fairness, and reciprocity strongly motivate many people. Moreover, several theoretical papers demonstrate that the observed phenomena can be explained in a rigorous and tractable manner. These theories then induced a first wave of experimental research which offered exciting insights into both the nature of preferences and the relative performance of competing fairness theories. The purpose of this chapter is to review these developments, to point out open questions, and to suggest avenues for future research. We also discuss recent neuroeconomic evidence that is consistent with the view that many people have a taste for mutual cooperation and the punishment of norm violators. We further illustrate the powerful impact of fairness concerns on cooperation, competition, incentives, and contract design.

Pathophysiology of polytrauma.

Abstract: Immediate and early trauma deaths are determined by primary brain injuries, or significant blood loss (haemorrhagic shock), while late mortality is caused by secondary brain injuries and host defence failure. First hits (hypoxia, hypotension, organ and soft tissue injuries, fractures), as well as second hits (e.g. ischaemia/reperfusion injuries, compartment syndromes, operative interventions, infections), induce a host defence response. This is characterized by local and systemic release of pro-inflammatory cytokines, arachidonic acid metabolites, proteins of the contact phase and coagulation systems, complement factors and acute phase proteins, as well as hormonal mediators: it is defined as systemic inflammatory response syndrome (SIRS), according to clinical parameters. However, in parallel, anti-inflammatory mediators are produced (compensatory anti-inflammatory response syndrome (CARS). An imbalance of these dual immune responses seems to be responsible for organ dysfunction and increased susceptibility to infections. Endothelial cell damage, accumulation of leukocytes, disseminated intravascular coagulation (DIC) and microcirculatory disturbances lead finally to apoptosis and necrosis of parenchymal cells, with the development of multiple organ dysfunction syndrome (MODS), or multiple organ failure (MOF). Whereas most clinical trials with anti-inflammatory, anti-coagulant, or antioxidant strategies failed, the implementation of pre- and in-hospital trauma protocols and the principle of damage control procedures have reduced post-traumatic complications. However, the development of immunomonitoring will help in the selection of patients at risk of post-traumatic complications and, thereby, the choice of the most appropriate treatment protocols for severely injured patients.

Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis.

Abstract: Immunization with myelin antigens leads to the development of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. The disease can also be induced by the transfer of encephalitogenic CD4+ T helper (T(H)) lymphocytes into naive mice. These T cells need to re-encounter their cognate antigen in the context of major histocompatibility complex (MHC) class II-bearing antigen-presenting cells (APCs) in order to recognize their target. The cell type and location of the APC mediating T-cell entry into the central nervous system (CNS) remain unknown. Here, we show that APCs of the lymphoreticular system and of the CNS parenchyma are dispensable for the immune invasion of the CNS. We also describe that a discrete population of vessel-associated dendritic cells (DCs) is present in human brain tissue. In mice, CD11c+ DCs alone are sufficient to present antigen in vivo to primed myelin-reactive T cells in order to mediate CNS inflammation and clinical disease development.

Engineering novel binding proteins from nonimmunoglobulin domains

Abstract: Not all adaptive immune systems use the immunoglobulin fold as the basis for specific recognition molecules: sea lampreys, for example, have evolved an adaptive immune system that is based on leucine-rich repeat proteins. Additionally, many other proteins, not necessarily involved in adaptive immunity, mediate specific high-affinity interactions. Such alternatives to immunoglobulins represent attractive starting points for the design of novel binding molecules for research and clinical applications. Indeed, through progress and increased experience in library design and selection technologies, gained not least from working with synthetic antibody libraries, researchers have now exploited many of these novel scaffolds as tailor-made affinity reagents. Significant progress has been made not only in the basic science of generating specific binding molecules, but also in applications of the selected binders in laboratory procedures, proteomics, diagnostics and therapy. Challenges ahead include identifying applications where these novel proteins can not only be an alternative, but can enable approaches so far deemed technically impossible, and delineate those therapeutic applications commensurate with the molecular properties of the respective proteins.

Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands

Abstract: The insulin/insulin-like growth factor-like signaling pathway, present in all multicellular organisms, regulates diverse functions including growth, development, fecundity, metabolic homeostasis, and lifespan. In flies, ligands of the insulin/insulin-like growth factor-like signaling pathway, the Drosophila insulin-like peptides, regulate growth and hemolymph carbohydrate homeostasis during development and are expressed in a stage- and tissue-specific manner. Here, we show that ablation of Drosophila insulin-like peptide-producing median neurosecretory cells in the brain leads to increased fasting glucose levels in the hemolymph of adults similar to that found in diabetic mammals. They also exhibit increased storage of lipid and carbohydrate, reduced fecundity, and reduced tolerance of heat and cold. However, the ablated flies show an extension of median and maximal lifespan and increased resistance to oxidative stress and starvation.

Microbial status of apical root canal system of human mandibular first molars with primary apical periodontitis after “one-visit” endodontic treatment

Abstract: Objective To assess the in vivo intracanal microbial status of apical root canal system of mesial roots of human mandibular first molars with primary apical periodontitis immediately after one-visit endodontic treatment. The residual intracanal infection was confirmed by correlative light and transmission electron microscopy. Study design Sixteen diseased mesial roots of mandibular first molars were treated endodontically, each in one visit. Mesio-buccal canals were instrumented using stainless steel hand files and mesio-lingual canals with a nickel-titanium rotary system. The canals were irrigated with 5.25% sodium hypochlorite (NaOCl) during the instrumentation procedures, rinsed with 10 mL of 17% ethylenediamine tetraacetic acid (EDTA), and obturated with gutta-percha and zinc oxide eugenol cement. Thereafter, the apical portion of the root of each tooth was removed by flap-surgery. The specimens were fixed, decalcified, subdivided in horizontal plane, embedded in plastic, processed, and evaluated by correlative light and transmission electron microscopy. Results Fourteen of the 16 endodontically treated teeth revealed residual intracanal infection after instrumentation, antimicrobial irrigation, and obturation. The microbes were located in inaccessible recesses and diverticula of instrumented main canals, the intercanal isthmus, and accessory canals, mostly as biofilms. Conclusions The results show (1) the anatomical complexity of the root canal system of mandibular first molar roots and (2) the organization of the flora as biofilms in inaccessible areas of the canal system that cannot be removed by contemporary instruments and irrigation alone in one-visit treatment. These findings demonstrate the importance of stringent application of all nonantibiotic chemo-mechanical measures to treat teeth with infected and necrotic root canals so as to disrupt the biofilms and reduce the intraradicular microbial load to the lowest possible level so as to expect a highly favorable long-term prognosis of the root canal treatment.

A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration

Abstract: A new system for lineage ablation is based on transgenic expression of a diphtheria toxin receptor (DTR) in mouse cells and application of diphtheria toxin (DT). To streamline this approach, we generated Cre-inducible DTR transgenic mice (iDTR) in which Cre-mediated excision of a STOP cassette renders cells sensitive to DT. We tested the iDTR strain by crossing to the T cell- and B cell-specific CD4-Cre and CD19-Cre strains, respectively, and observed efficient ablation of T and B cells after exposure to DT. In MOGi-Cre/iDTR double transgenic mice expressing Cre recombinase in oligodendrocytes, we observed myelin loss after intraperitoneal DT injections. Thus, DT crosses the blood-brain barrier and promotes cell ablation in the central nervous system. Notably, we show that the developing DT-specific antibody response is weak and not neutralizing, and thus does not impede the efficacy of DT. Our results validate the use of iDTR mice as a tool for cell ablation in vivo.

Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension

Abstract: Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.

Experimental autoimmune encephalomyelitis repressed by microglial paralysis.

Abstract: Although microglial activation occurs in inflammatory, degenerative and neoplastic central nervous system (CNS) disorders, its role in pathogenesis is unclear. We studied this question by generating CD11b-HSVTK transgenic mice, which express herpes simplex thymidine kinase in macrophages and microglia. Ganciclovir treatment of organotypic brain slice cultures derived from CD11b-HSVTK mice abolished microglial release of nitrite, proinflammatory cytokines and chemokines. Systemic ganciclovir administration to CD11b-HSVTK mice elicited hematopoietic toxicity, which was prevented by transfer of wild-type bone marrow. In bone marrow chimeras, ganciclovir blocked microglial activation in the facial nucleus upon axotomy and repressed the development of experimental autoimmune encephalomyelitis. We conclude that microglial paralysis inhibits the development and maintenance of inflammatory CNS lesions. The microglial compartment thus provides a potential therapeutic target in inflammatory CNS disorders. These results validate CD11b-HSVTK mice as a tool to study the impact of microglial activation on CNS diseases in vivo.